A convergent approach toward the C1-C11 subunit of phoslactomycins and formal synthesis of phoslactomycin b

Article abstract of DOI:10.1021/ol8029142

The preparation of the C1-C11 subunit of phoslactomycins, and a formal synthesis of phoslactomycin B, were achieved by a convergent strategy involving the chelation-controlled addition of an alkynyl Grignard reagent to an α-alkoxy ketone. Catalytic enanti

Full text of DOI:10.1021/ol8029142

ORGANIC
LETTERS
2009
Vol. 11, No. 4
935-938
A Convergent Approach toward the
C1-C11 Subunit of Phoslactomycins
and Formal Synthesis of
Phoslactomycin B
Vale´rie Druais,† Michael J. Hall,† Camilla Corsi,‡ Sebastian V. Wendeborn,‡
Christophe Meyer,*,† and Janine Cossy*,†
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue Vauquelin,
75231 Paris Cedex 05, France, and Syngenta Crop Protection Muenchwilen AG,
WST-820.2.15, Schaffhauserestrasse, 4332 Stein, Switzerland
christophe.meyer@espci.fr; janine.cossy@espci.fr
Received December 18, 2008
ABSTRACT
The preparation of the C1-C11 subunit of phoslactomycins, and a formal synthesis of phoslactomycin B, were achieved by a convergent
strategy involving the chelation-controlled addition of an alkynyl Grignard reagent to an r-alkoxy ketone. Catalytic enantioselective reductions
of acetylenic ketones and a [2,3]-Wittig rearrangement were utilized as key steps to control the configuration of the C4, C5, and C9 stereocenters.
Phoslactomycins (PLMs) A-F, isolated in 1989 from the
culture broth of a strain of Streptomyces nigrescens, were
found to exhibit potent activity against phytopathogenic
fungi.1 These compounds share a common backbone includ-
ing a R,ꢀ-unsaturated δ-lactone, a disubstituted alkene of
(E) configuration (C6-C7), a tertiary alcohol at C8 substi-
tuted by a 2-aminoethyl chain, a phosphate at C9, a secondary
alcohol at C11, and a conjugated (Z,Z)-diene (C12-C15)
with a cyclohexyl group at C15 but differ by the substituent
at C18 on the latter cyclohexane ring. Phospholine (PLM
B) was isolated from the fermentation broth of a strain of
Figure 1. Phoslactomycins (PLMs) and Leustroducsins (LSNs).
Streptomyces hygroscopicus and potent activities against
L1210, P388 and EL4 murine cancer cell lines were reported
for this compound.2 In 1993, the structurally related leus-
troducsins (LSNs) A-C, isolated from the culture broth of
Streptomyces platensii (SANK 60191), were found to possess
colony-stimulating factors inducing activity.3 The mode of
action of PLMs and LSNs4 seems to derive from the selective
inhibition of serine-threonine phosphatase 2A,5 an enzyme
involved in the regulation of many crucial biological events
(Figure 1).6
† ESPCI ParisTech.
‡ Syngenta Crop Protection.
(1) (a) Fushimi, S.; Nishikawa, S.; Shimazu, A.; Seto, H. J. Antibiot.
1989, 42, 1019–1025. (b) Fushimi, S.; Furihata, K.; Seto, H. J. Antibiot.
Chem. 1989, 42, 1026–1036.
10.1021/ol8029142 CCC: $40.75
Published on Web 01/26/2009
2009 American Chemical Society

To date, two total syntheses of PLM B7,8 and LSN B9,10
as well as one formal synthesis of the latter compound have
been reported.11 Evans aldol reactions7,9 or Brown-type
pentenylation8,11 have essentially been used to control the
configuration of the C4 and C5 stereocenters. Alternatively,
a Sharpless asymmetric epoxidation followed by ring-
opening of the resulting epoxide with an alkynylalane has
also been described.10 The 1,2-diol at C8-C9 has often been
installed by a Sharpless asymmetric dihydroxylation,8,10,11
and an interesting enzymatic desymmetrization of a meso-
1,3-diol has also been used to control the absolute configu-
ration of C8.9 Interestingly, in one total synthesis of PLM
B, the chelation-controlled addition of vinylmagnesium
bromide to a ketone at C8 was described. However, several
steps were subsequently required to create the C4 and C5
stereocenters and elaborate the disubstituted unsaturated
lactone from the introduced vinyl group.7a,12
configuration of the C8 stereocenter.13 Additionally, the use
of new key steps was considered to create the C4, C5, and
C9 stereocenters in this family of natural products. A [2,3]-
Wittig rearrangement of the allylic and propargylic ether of
type D, operating with chirality tranfer, would be used to
control the configuration of C4 and C5.14 Although any R
substituent could in principle be used, an allyloxymethyl
group was selected in order to act as a relay during the
RCM.15 Ketone C would be prepared from the propargylic
alcohol E by regioselective copper-catalyzed cyclo-func-
tionalization using tosyl isocyanate. Thus, the configurations
of C4, C5, and C9 would all be controlled, either in an
indirect or a direct manner, respectively, by catalytic enan-
tioselective reductions of acetylenic ketones (Scheme 1).
Scheme 1. Retrosynthetic Analysis of the C1-C11 Subunit
Herein, we report a new convergent approach toward the
C1-C11 subunit of PLMs and a formal synthesis of PLM
B, relying on the formation of the C7-C8 bond.
In our retrosynthetic analysis, the C1-C11 fragment of
the PLMs A was disconnected at the C7-C8 bond and the
construction of the unsaturated lactone was envisaged by
ring-closing metathesis (RCM). The goal was to achieve the
chelation-controlled addition of an alkenyl or an alkynyl
Grignard reagent of type B, precursor of the C1-C7 segment
and already containing the C4 and C5 stereocenters, to a
suitably protected R-alkoxy ketone C in order to control the
(2) (a) Ozasa, T.; Suzuki, K.; Sasamata, M.; Tanaka, K.; Kobori, M.;
Kadota, S.; Nagai, K.; Saito, T.; Watanabe, S.; Iwanami, M. J. Antibiot.
Chem. 1989, 42, 1331–1338. (b) Ozasa, T.; Tanaka, K.; Sasamata, M.;
Kaniwa, H.; Shimizu, M.; Matsumoto, H.; Iwanami, M. J. Antibiot. Chem.
1989, 42, 1339–1343
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A. J. Antibiot. Chem. 1993, 46, 1503–1511. (b) Kohama, T.; Nakamura,
T.; Kinoshita, T.; Kaneko, I.; Shiraishi, A. J. Antibiot. Chem. 1993, 46,
1512–1519. (c) Shibata, T.; Kurihara, S.; Yoda, K.; Haruyama, H.
The synthesis of the C3-C7 subunit was carried out from
the readily available R-allyloxyacetic acid 1,16 which was
converted to a Weinreb amide,17 and subsequent addition
of but-1-ynyllithium led to the acetylenic ketone 2 (71%,
two steps from 1). The chirality was introduced through an
enantioselective reduction of ketone 2, catalyzed by ruthe-
nium complex (S,S)-Ru-I (5 mol %) in i-PrOH,18 to provide
the optically active propargylic alcohol 3 (97%, ee ) 91%).19
Stereoselective reduction of the alkyne using a zinc-copper
couple (THF/i-PrOH, reflux)20 generated the corresponding
(Z)-allylic alcohol which was alkylated with (triisopropyl-
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Sasagawa, K.; Kobayashi, T.; Kohama, T.; Asai, F.; Shiraishi, A.; Sugimura,
.
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(b) Marshall, J. A. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: London, 1991; Vol. 3, pp 975-908.
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Hosokawa, T.; Ikejiri, M.; Imanishi, T. J. Org. Chem. 2008, 73, 5360–
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(12) The chelation-controlled addition of an alkenyl Grignard reagent
to a methyl ketone has been used in several convergent syntheses of the
structurally related natural product fostriecin, see: (a) Chavez, D. E.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2001, 40, 3667–3670. (b) Wang,
Y.-G.; Kobayashi, Y. Org. Lett. 2002, 4, 4615–4618. (c) Trost, B. M.;
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Soc. 1997, 119, 8738–8739.
(19) The ee was determined by super-critical fluid chromatography
analysis (chiral phase), see the Supporting Information.
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1984, 735–736.
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Org. Lett., Vol. 11, No. 4, 2009

silyl)propargyl bromide21 to afford propargylic ether 4 (84%,
two steps from 3). The C4 and C5 stereocenters were then
created by the [2,3]-Wittig rearrangement of the optically
active allylic and propargylic ether 4 (n-BuLi, THF,
-78 °C). The propargylic and homoallylic alcohol 5 was
isolated as a single diastereomer in almost quantitative
yield.22 The observed stereochemical outcome is in agree-
ment with a five-membered-ring transition state of envelope
conformation wherein the allylyoxymethyl chain preferen-
tially occupies a pseudoequatorial position, while an exo
orientation is favored for the π-donating stabilizing alkynyl
group.23 Desilylation of the terminal alkyne provided com-
pound 6 (100%), which corresponds to the C3-C7 subunit
of the PLMs. Its preparation has thus been achieved in seven
steps from R-allyloxyacetic acid (57% overall yield) (Scheme
2).
amount of CuI and Et3N (THF, reflux) to produce the
N-tosyl-4-(alkylidene)oxazolidin-2-one 9 (92%) as a single
geometric isomer.24 Hydrolysis of compound 9 under care-
fully controlled alkaline conditions (1 M NaOH/THF) led
to the desired R-hydroxy ketone 10 in good yield (76%,
ee g 94%).19,25 Finally, protection of the hydroxyl group as
a MOM ether afforded the R-alkoxy ketone 11 in almost
quantitative yield.26 This compound, which corresponds to
the C8-C11 subunit, has been prepared in eight steps from
propane-1,3-diol (38% overall yield) (Scheme 3).
Scheme 3. Synthesis of the C8-C11 Subunit
Scheme 2. Synthesis of the C3-C7 Subunit
The coupling of the two fragments was then investigated.
Initial efforts to couple alkenyl Grignard reagents, incorpo-
rating a precursor of the C1-C7 subunit, with R-alkoxy
ketones bearing a 2-alkoxyethyl chain were discouraging.
Little addition occurred, and enolization was observed as a
side reaction.
For this reason, the use of a less hindered (and less basic)
alkynyl Grignard reagent was considered. Thus, treatment
of propargylic alcohol 6 with i-PrMgCl (2 equiv) generated
an alkynyl Grignard reagent which smoothly reacted with
ketone 11 to afford the tertiary alcohol 12 (84% yield based
on 11) with good diastereoselectivity (dr ) 92/8), as a result
of a chelate control exerted by the alkoxy (OMOM)-
substituted C9 stereocenter.13 An excess of the Grignard
reagent was conveniently used (3.5 equiv) to ensure complete
conversion of ketone 11, and the excess of terminal alkyne
6 could be quantitatively recovered and recycled. Stereo-
selective hydroalumination of the alkyne with Red-Al27 and
The preparation of the C8-C11 fragment was carried out
from ketone 7, which is readily available from propane-1,3-
diol through a series of straightforward operations (four steps,
61% overall yield). Enantioselective reduction of the acety-
lenic ketone 7, catalyzed by ruthenium complex (R,R)-Ru-I
(5 mol %) [i-PrOH/CH2Cl2 (10/1), rt], afforded the optically
active propargylic alcohol 8 (89%, ee ) 97%).18 The formal
regioselective hydration of the disubstituted alkyne, required
to convert compound 8 into an R-alkoxy ketone of type C,
was achieved through cyclofunctionalization. Alcohol 8 was
treated with tosyl isocyanate in the presence of a catalytic
(24) Ohe, K.; Ishihara, T.; Chatani, N.; Kawasaki, Y.; Murai, S. J. Org.
Chem. 1991, 56, 2267–2268.
(21) Wright, J. M.; Jones, G. B. Tetrahedron Lett. 1999, 40, 7605–7609.
(22) For recent applications of [2,3]-Wittig rearrangements to the
preparation of polypropionate subunits, see: (a) Parker, K. A.; Xie, Q. Org.
Lett. 2008, 10, 1349–1352. (b) Cao, H.; Parker, K. A. Org. Lett. 2008, 10,
1353–1356.
(25) For the use of this strategy to prepare an R-hydroxy ketone bearing
a tertiary alcohol, see: Matsuura, T.; Nishiyama, S.; Yamamura, S. Chem.
Lett. 1993, 1503–1504
(26) Protection as a PMB ether was unsuccessful under various reaction
conditions.
.
(23) (a) Wu, Y.-D.; Houk, K. N.; Marshall, J. A. J. Org. Chem. 1990,
55, 1421–1423. (b) Mikami, K.; Uchida, T.; Hirano, T.; Wu, Y.-D.; Houk,
K. N. Tetrahedron 1994, 50, 5917–5926.
(27) Chan, K.-K.; Cohen, N.; De Noble, J. P.; Specian, A. C., Jr.; Saucy,
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Org. Lett., Vol. 11, No. 4, 2009
937

Scheme 4. Preparation of the C1-C11 Fragment of the Phoslactomycins. Formal Synthesis of Phoslactomycin B
subsequent condensation of the secondary allylic alcohol at
C5 with acryloyl chloride provided acrylate 13 (62%, two
steps from 12). The formation of the unsaturated lactone was
next achieved by a relay ring-closing metathesis,15 catalyzed
by Grubbs second-generation catalyst,28 during which di-
hydrofuran was expelled and the R,ꢀ-unsaturated lactone 14
was produced in 88% yield.29,30 Conversion of lactone 14
into the target C1-C11 subunit of PLMs was achieved in
four steps by cleavage of the trityl group, mesylation of the
resulting primary alcohol, and displacement of the mesylate
with sodium azide. Subsequent Staudinger reaction followed
by in situ acylation of the primary amine with allyl
chloroformate finally led to compound 15 (29% overall yield
from 14), which constitutes the C1-C11 subunit of PLMs
in our convergent synthetic approach toward this family of
natural products. To confirm the structural and stereochemical
assignments made for compound 15, the secondary and
primary hydroxyl groups in the latter compound were
deprotected (aq 6 M HCl/THF, rt), and protection of the three
alcohols as a triethylsilyl ethers led to compound 16 (40%),
whose spectroscopic data matched with those previously
reported for the same advanced intermediate in Hatakeyama’s
total synthesis of PLM B (Scheme 4).8
In conclusion, we have reported the synthesis of the
C1-C11 subunit of the PLMs by a convergent route
involving the diastereoselective addition of an alkynyl
Grignard reagent, incorporating an elaborate precursor of the
C1-C7 fragment, to an R-alkoxy ketone. The key steps
involved in the control of the configuration of the C4, C5,
and C9 stereocenters are ruthenium-catalyzed enantio-
selective reductions of acetylenic ketones and a highly dia-
stereoselective [2,3]-Wittig rearrangement. Also noteworthy
is the use of a copper-catalyzed cyclofunctionalization of a
chiral propargylic alcohol since, to our knowledge, it is the
first report on the use of this strategy to generate an optically
active R-hydroxy ketone bearing a secondary alcohol.25
(28) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
6, 953–956.
(29) Treatment of 13 with Grubbs II (5 mol %, CH2Cl2, reflux 2 h) led
the desired lactone 14 (75%) and the corresponding terminal alkene at C3
(25%). The RCM of the latter compound subsquently proceeded at a much
slower rate and required a higher catalyst loading to reach completion, thus
highlighting the interest of the relay RCM.
Acknowledgment. Syngenta Crop Protection is gratefully
acknowledged for financial support. V.D. thanks the MRES
for a grant.
Supporting Information Available: Experimental pro-
cedures and 1H and 13C NMR data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(30) The coupling constant value between H4 and H5 (3JH4-H5 ) 4.6
Hz) confirmed the relative configuration of C4 and C5; see ref 6 and:
(a) Bialy, L.; Lopez-Canet, M.; Waldmann, H. Synthesis 2002, 2096–2104.
(b) Salit, A.-F.; Meyer, C.; Cossy, J.; Delouvrie´, B.; Hennequin, L.
Tetrahedron 2008, 64, 6684–6697
.
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